Polycystin-2 in the Endoplasmic Reticulum: Bending Ideas about the Role of the Cilium
Authors: Michael J. Caplan
Journal: Journal of the American Society of Nephrology (2022)

As is the case for many of nature's most elegant structures, the utility of the cilium extends beyond its biologic functions into the realm of metaphor. Although it is drawn in most textbooks as a neatly symmetrical entity, constructed of parallel straight lines, our appreciation for the cilium derives primarily from its ability to bend. Only when it abandons the constraints of artistically imposed rigidity can the cilium create motion or sense and communicate it. The same can perhaps be said about our conceptions of how the primary cilium's capacity to respond to shear forces may relate to the pathogenesis of human disease. Just over 20 years ago, Helle Praetorius and Ken Spring made the seminal discovery that the primary cilium can function as a flow sensor whose mechanical deformation leads to modulation of ion conductances.1 Very shortly thereafter, it was shown that the cilium is home to subpopulations of Polystin1 and Polycystin-2, the proteins encoded by the Pkd1 and Pkd2 genes that are associated with most patients with autosomal dominant polycystic kidney disease.2 The molecular cloning of the Pkd2 gene revealed that Polycystin-2 is a member of the Transient Receptor Potential (TRP) family of cation channels, which plays a critical role in a large number of chemical and physical sensory phenomena.2 A key paper by Surya Nauli, Jing Zhou, and their colleagues laid the groundwork for the idea that the channel function of Polycystin-2 contributes to the mechanosensory properties of the cilium,3 and, although this model has evolved over the ensuing two decades, it continues to inform our understanding of the role of the ciliary pools of the Polycystin proteins in renal epithelial cells.4 Although the data that Polycystins participate in ciliary mechanosensation are quite strong, there is less direct experimental proof for the widely held belief that it is this involvement in ciliary mechanosensation that constitutes the primary physiologic role of Polycystin-2, the loss of which leads to the development of cystic disease. The exciting and surprising results reported in this issue of he Journal of the American Society of Nephrology by Padhy et al.5 strongly suggest the time has come for this presumption to emulate the cilium, and thus to bend. Although the ciliary contingent of Polycystin-2 has understandably come to command much of the attention of the autosomal dominant polycystic kidney disease field, it has long been recognized that largest population of Polycystin-2 protein resides in the endoplasmic reticulum in renal epithelial cells.6 Furthermore, early studies of the channel function of Polycystin-2 demonstrated it could participate in calcium release from the endoplasmic reticulum.7 Studies of the channel activity of native Polycystin-2 endogenously expressed in renal cilia4 and of a gain of function mutant form of Polycystin-2 expressed in cultured cells by transfection8 indicate that, at least under the conditions of these experiments, monovalent cations carry the majority of Polycystin-2–associated currents. Padhy et al.5 show Polycystin-2 functions as an endoplasmic reticulum potassium channel whose activity is required to shunt the current associated with IP3-induced calcium release from the endoplasmic reticulum. The authors demonstrate that in cultured cells, the loss of Polycystin-2 expression suppresses stimulated endoplasmic reticulum calcium release, and this activity can be rescued by expressing the endoplasmic reticulum–localized potassium channel TricB. Similarly, the impaired calcium release that is associated with loss of TricB expression is rescued by Polycystin-2. Expression of active (but not inactive) TricB or endoplasmic reticulum–targeted ROMK potassium channels, or a Polycystin-2 mutant that is excluded from the cilium, partially rescued the tail curvature phenotypes observed in Polycystin-2–morphant zebrafish. Most strikingly, transgenic expression of TricB2 in a mouse model of conditional loss of Polycystin-2 expression ameliorated the severity of cystic disease. Conversely, induced loss of TricB expression led to some cyst formation in Pkd2 heterozygous mice. The authors conclude that the primary physiologic function of Polycystin-2, at least as it relates to the pathogenesis of renal cystic disease, is to serve as an endoplasmic reticulum monovalent cation channel whose activity is required to provide charge balance for IP3-induced endoplasmic reticulum calcium release. Furthermore, replacing the endoplasmic reticulum, but not the ciliary activities of Polycystin-2, is sufficient to suppress aspects of cystic disease. Previous studies have explored the functional interaction between the IP3 receptor and Polycystin-2, and demonstrated that, in cultured epithelial cells grown in a three-dimensional matrix, loss of IP3 receptor function can prompt cyst growth that mirrors or exceeds that which occurs when Polycystin-2 expression is disrupted.9 The mechanism through which perturbed calcium release from the endoplasmic reticulum might lead to, or at least amplify, the development of cystic disease is not at all clear. It is interesting to speculate, however, that an obligate role for Polycystin-2 in endoplasmic reticulum calcium release could account, at least in part, for aspects of the perturbed mitochondrial function that characterize cells that lack Polycystin expression.10 Calcium released from the endoplasmic reticulum at sites of close apposition between the endoplasmic reticulum and mitochondria is taken up by those mitochondria and plays a critical role in regulating the level of mitochondrial oxidative phosphorylation. The Polycystin proteins localize to the mitochondrial associated regions of the endoplasmic reticulum and participate in the modulation of mitochondrial calcium entry and mitochondrial energy generation in an oxygen-regulated fashion.10 More work will be required to determine whether the connection between perturbed endoplasmic reticulum calcium release and cyst formation is related to the roles of the Polycystin proteins in modulating mitochondrial function. It also remains to be seen whether or how the ciliary and endoplasmic reticulum cohorts of Polycystin-2 protein may act in concerted pathways or communicate with one another. The fascinating results presented in the paper by Padhy et al.5 do not in any way diminish the potential physiologic importance of ciliary Polycystin-2, nor do they reduce the value of exploring the signaling processes in which ciliary Polycystin-2 participates. These studies do, however, challenge the prevailing concept that loss of ciliary Polycystin-2 is a primary contributor to the development of cystic disease. Although much remains to be learned about the relationship between Polycystin-2, endoplasmic reticulum calcium release and the mechanisms of cyst formation, it is likely the thoughtful discussions that will be catalyzed by the rather remarkable results reported in this paper will substantially advance the field. Disclosures M. Caplan reports Consultancy: NFold Pharmaceuticals, Maze Therapeutics; Ownership Interest: NFold Pharmaceuticals; Honoraria: Novartis, Novo Nordisk, Johnson and Johnson; Patents or Royalties: NFold Pharmaceuticals; and Advisory or Leadership Role: Telethon Italia (an Italian not for profit charity that supports research on monogenetic disease), and American Physiological Society (Editor in Chief, "Physiology"). Funding This work is supported by National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases grants DK120534 and DK072612, and US Department of Defence grant PR191158.